Cognition Therapeutics Inc.'s mission is to develop effective therapeutics for Alzheimer's disease (AD). Recent scientific discoveries have identified oligomers of the brain protein A?42 as toxic culprits in disease progression. Cognition, in partnership with Temple University, has identified a novel series of sigma-2 receptor binding modulators that displace oligomers from neurons and block the downstream pathological signaling that inhibits memory formation. These therapeutics should prevent further A?42 oligomer-induced damage, and unmask existing memory capacity as synapses recover. These receptor binding modulators are hypothesized to be disease-modifying treatments that would be effective throughout the course of the disease, and significantly impact the lives of the millions of Alzheimer's patients. Pharmaceutical industry efforts targeted specifically at A?42 oligomer displacement are currently limited. Cognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule A?42 oligomer displacing therapeutics. We have discovered two CNS drug-like lead series of A?42 oligomer displacing compounds, Analogs in these series displace oligomers from neurons and completely block A?42 oligomer-induced membrane trafficking changes and synapse loss. Members of these series are highly brain-penetrant and completely block oligomer-induced memory deficits in Alzheimer's disease mouse models. Development of a clinical candidate is progressing. We have now turned our attention to identifying new candidates to provide a measure of risk mitigation in the event that our current candidate falters due to unforeseen issues. We propose to optimize Temple University's series of novel sigma-2 receptor binding modulators by synthesis and testing of new analogs designed to improve pharmacological and ADME properties. This proposal will allow us to expand our portfolio of sigma-2 receptor binding modulators with the goal of identifying orally efficacious candidates for further development as therapeutics for AD.